Liraglutide shows promise for weight loss in teens with obesity
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Adolescents with obesity who did not respond to lifestyle therapy saw a greater reduction in BMI standard deviation score during a 1-year intervention with the GLP-1 receptor agonist liraglutide compared with similar adolescents assigned placebo, according to findings from a randomized controlled trial accepted for presentation at the Endocrine Society Annual Meeting and published in The New England Journal of Medicine.
“The primary efficacy endpoint was met in this trial — treatment with liraglutide 3 mg for 56 weeks reduced BMI standard deviation score to a greater extent than placebo,” Aaron S. Kelly, PhD, a professor in the department of pediatrics and a co-director of the Center for Pediatric Obesity Medicine at the University of Minnesota Medical School in Minneapolis, told Healio. “Importantly, results were consistent and robust when looking at other BMI metrics, body weight and waist circumference, all of which were reduced more with liraglutide. In line with the view that obesity is a biologically driven disease requiring continuing management, we observed an increase in BMI after withdrawal of liraglutide treatment.”
In a randomized, double-blind trial, Kelly and colleagues analyzed data from 251 adolescents aged 12 to 18 years with obesity considered poor responders to lifestyle therapy alone from five countries: Belgium, Mexico, Russia, Sweden and the United States. During a 12-week run-in period, all participants received counseling on healthy nutrition and physical activity for weight loss. Between September 2016 and August 2018, researchers randomly assigned participants to liraglutide 3 mg (Saxenda, Novo Nordisk; n = 125; mean age, 15 years; 56.8% girls) or volume-matched placebo (n = 126; mean age, 15 years; 61.9% girls) subcutaneously once daily, in addition to lifestyle therapy for 56 weeks. A 26-week period without treatment followed. Primary endpoint was change from baseline in BMI standard deviation score (SDS) at week 56.
At 56 weeks, researchers found that liraglutide was superior to placebo for change from baseline in BMI SDS, with an estimated treatment difference of –0.22 (95% CI, –0.37 to –0.08).
“The estimated treatment difference in the mean reduction in the BMI standard deviation score that we observed in our trial of liraglutide was greater than differences observed in trials of lifestyle therapy conducted by the U.S. Preventive Services Task Force (–0.17) and in an overview of six Cochrane reviews (–0.13),” the researchers wrote in the study.
Additionally, compared with those assigned placebo, more participants in the liraglutide group experienced at least a 5% reduction in BMI (43.3% vs. 18.7%) and at least a 10% reduction in BMI (26.1% vs. 8.1%) during the study. BMI reduction was greater among adolescents assigned liraglutide vs. placebo, with an estimated difference of –4.64 percentage points at 56 weeks (95% CI, –7.14 to –2.14). Similarly, loss of body weight was greater in the liraglutide group vs. placebo, with an estimated difference of –4.5 kg for absolute change and –5.01 percentage points for relative change.
“We believe that the degree of BMI reduction with liraglutide 3 mg was clinically meaningful,” Kelly said. “The U.S. Preventive Services Task Force deemed a BMI SDS reduction of at least 0.2 as clinically significant. Though the trial design and statistical analysis differed from the adult phase 3 trials of liraglutide 3 mg, the placebo-subtracted body weight reduction was similar (between 5% and 5.5% in each), and the safety profile in adolescents appears similar to what has been observed in the adult trials of liraglutide 3 mg.”
Consistent with the safety profile of GLP-1 receptor agonists, more participants in the liraglutide group reported gastrointestinal adverse events vs. placebo (64.8% vs. 36.5%; P < .001) and adverse events that led to discontinuation of treatment (10.4% vs. 0).
One suicide, which occurred in the liraglutide group, was assessed by the investigator as unlikely to be related to the trial treatment, according to researchers.
The researchers noted the multinational study population and high retention rate (> 80%) as study strengths, but cited a lack of measurements of body composition and other potentially relevant cardiometabolic variables, as well as limited power to detect differences in secondary outcomes of cardiometabolic markers as study limitations.
“In contrast to trials involving adults and to an observational trial involving adolescents, our trial showed no substantial differences between the liraglutide group and the placebo group in cardiometabolic markers or results on quality of life assessments,” the researchers wrote. “These results could be due to the fact that most participants had baseline variables within the normal range or could reflect the limited sample size, which was selected on the basis of power calculations relevant to the BMI standard deviation score.” – by Regina Schaffer
References:
Kelly AS, et al. OR33-01. The Endocrine Society Annual Meeting; 2020 (conference canceled/virtual meeting).
Kelly AS, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa1916038.
Disclosures: Novo Nordisk funded and designed this study. Kelly reports he serves as an unpaid consultant for Novo Nordisk, Vivus and Weight Watchers, and has received drug/placebo from AstraZeneca for a National Institute of Diabetes and Digestive and Kidney Diseases-funded clinical trial. Please see the study for all other authors’ relevant financial disclosures.
Perspective
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Ken Fujioka, MD
It is great to see a potential treatment for growing adolescents that looks very safe. This type of study is difficult to conduct — and often does not look as impressive — because these kids are still growing, so you expect some gain in height and weight. About half the kids were Tanner stage 5, meaning very close to their adult height and maturity from a sexual standpoint; however, about half were not fully sexually mature, meaning they are still growing. Here the authors use BMI to help demonstrate improvement, as BMI takes into account both height and weight.
These are very impressive changes in the right direction with liraglutide, with no signs of any significant adverse effects. Adolescents with obesity have very few options. Here the mean BMI was 35 kg/m², which is very high, and for adults, often qualifies for bariatric surgery. To see excellent weight management with a physiologic agent like liraglutide along with no safety signal meets a very big unmet need.
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